ProjectSummary/Abstract Theincreasedriskofbreastcancerduetoworkingnightsorrotatingshiftshasbeenattributedto disruptionofcircadianrhythms,chronicsleeploss,nighttimelightexposure,melatoninsuppression,and chronic stress and fatigue. Because shift work can alter these variables simultaneously, human studies have been unable to determine the relative contributions of these variables to increased cancer risk. Several studies in rodent cancer models have purported to show that circadian rhythm disruption increases cancer progression. Unfortunately, all of the methods used to disrupt rhythms also produce chronic sleep loss, melatonin suppression, and increased stress hormones, each of which is capable of promoting tumor growth and proliferation. Therefore, the results of those animal studies cannot be strictlyattributedtocircadiandisruption.Todate,thereisnotasingleanimalstudythathasisolatedthe effects of circadian disruption on cancer without these confounds. We believe that a new animal model isneededtoaddressthisproblem. Wecaneliminatetheseconfoundsanddirectlyaddresstheroleofthecircadiansystemintumor development and progression by employing a new animal model, the circadian-arrhythmic Siberian hamster(Phodopussungorus).Thismodelwasdevelopedinourlaboratoryoverthepast20yearsand is uniquely suited for this project because circadian timing can be eliminated without impairing sleep or inducing stress. Circadian timing is eliminated by a single photic treatment that we have termed, the Disruptive Phase Shift (DPS) protocol. This protocol eliminates the need to ablate the SCN or alter geneexpression,thusleavingtheanimalsarrhythmic,butneurologicallyandgeneticallyintact.Thus,we can directly evaluate the contribution of circadian disruption to tumor development and progression by completelyshuttingoffcircadiantiming,andwithoutimpairingsleeporinducingstress. We have chosen to investigate the role of circadian disruption in a breast cancer model where tumors are induced by the carcinogen N-methyl-N-nitrosurea (NMU;? MNU). This is a widely used and well-established model of human breast cancer that works well in our hamsters. NMU is highly specific formammarytissueandtumorscanbeinducedbyasingleinjectionofthecarcinogen.Weproposeto: 1) definitively establish whether the loss of circadian timing (without impairing sleep) increases tumor development, 2) determine whether melatonin suppression that accompanies circadian-arrhythmia increases tumor development, and 3) use a scheduled feeding paradigm to ameliorate the effects of circadianarrhythmiaontumordevelopment.